The invention relates to androgen receptor-ablative agents and methods of using such agents for the treatment of cancer. Mounting evidence indicates that dysregulation of androgen receptor (AR) through gene amplification or mutations plays a key role in the development of androgen-refractory prostate cancer, a hallmark of incurable and lethal prostate cancer progression. These molecular changes enhance AR sensitivity or permit AR activation by antiestrogen, thus allowing prostate cancer cells to become resistant to androgen ablation-induced apoptosis. From a clinical perspective, targeting AR expression represents an important strategy to improve the treatment of androgen-independent prostate cancer and ultimately to increase the survival of prostate cancer patients.
A recent study indicates that knocking down the AR protein level by a small interfering RNA (siRNA) resulted in significant apoptotic cell death in LNCaP androgen-responsive prostate cancer cells, but not in the AR-null PC-3 cells. Moreover, in a LNCaP tumor xenograft model, short hairpin RNA (shRNA)-mediated AR knockdown was effective in blocking tumor growth and delaying tumor progression, which provides a proof-of-principle of this AR-targeted therapy. Studies have indicated that these AR-ablative agents mediate the transcriptional repression of androgen receptor through the downregulation of Sp1 expression. See Yang et al., Cancer Res., 67(7), p. 3229-3238 (2007). Since Sp1 has other target genes crucial to cancer cell survival, these agents could also suppress AR-independent cancer cell proliferation, and therefore provide anticancer effects beyond prostate cancer.
Although a number of natural product-based, small-molecule agents exhibit the ability to suppress AR expression, including resveratrol, vitamin E succinate, genistein, and curcumin, their therapeutic use in humans is limited by the high therapeutic concentration required by their low potency. Thus, there is an urgent need to develop potent AR-ablative agents to allow new strategies for cancer treatment, and in particular prostate cancer treatment.